Interrogation of Glioma Ontogeny using Mouse Models

Glioblastoma Multiforme (GBM) is the most common and lethal of human primary central nervous system tumours, with a median survival of 14-16 months despite surgery, radiation and chemotherapy. A reason for this dismal prognosis is insufficient understanding of the ontogeny of GBMs, which are highly heterogeneous at a pathological level. This pathological diversity, between and within GBMs as well as varying grades of gliomas, is not fully explained on the grounds of an oncogenic stimulus. Interaction with the tumour microenvironment, as well as inherent characteristics of the tumour cell of origin are likely a source of this heterogeneity. In this thesis we describe the use of a novel mouse model which integrates Cre-Lox mediated and Tet-regulated gene expression. This system in combination with germline and somatic strategies has enabled us to interrogate how the state in glial development and the region in the brain where transformation occurs influence the process of gliomagenesis. The findings of this thesis suggest that the state of glial development at which a mutation is introduced is an important determinant of gliomagenesis. In support of this, we showed that early progenitors in the radial glial lineage are more susceptible to transformation than those, which have committed to a gliogenic lineage and are presumably further along in the process of differentiation. Highlighting the interplay between genetic alterations and the molecular changes that accompany the process of differentiation. Despite findings that suggest that neurogenic regions of the adult brain are more susceptible to transformation, we show that this is not always the case and instead, transformation is dependent on an interaction between specific combinations of genetic mutations and susceptible cell types regardless of the region of origin. Results from this thesis highlight the need to view the tumourigenic process of gliomas in the context of normal brain development as the cell context of oncogene expression may determine the phenotype and biologic aggressiveness of the tumour. Thus, the results of genetic or epigenetic alterations leading to brain tumours may be quite different in different cells of the hierarchy, suggesting unique treatment targets and strategies depending on the cell of origin.Ph